The objective of this research proposal is the development of in vivo and in vitro models that permit the study of the clinical and pharmacological implications of the heterogeneity found in human tumors. We will study intraneoplastic diversity in a human colon xenograft (DLD-1) composed of 2 clones (A and D) which grows both in tissue culture and in the nude mouse. We will test the responsiveness of the parent xenograft and of each subclone to single and to combinations of chemotherapeutic agents and interpret the results according to a method of data analysis developed by one of us. The statistical model used allows determination of the optimal dose of each individual agent used in the combination, indicates the presence of important drug interactions, and permits placing toxicity constraints on the optimal doses chosen. We will design protocols that evaluate the effectiveness of treating with multiple agents given simultaneously versus sequentially in order to examine the relative effectiveness of these two strategic approaches. The drugs to be tested include agents employed in the clinical treatment of colon cancer, investigational agents showing some indication of activity against colon cancer and drugs known to be effective against DLD-1, Clone A or Clone D. In addition, since purine analogues are of special interest in our cancer center, we will design biochemically rational experiments by combining purine analogues with the adenosine deaminase inhibitor 2'deoxycoformycin. We will analyze the surviving cells after chemotherapeutic treatment of DLD-1 or of artificial mixtures of Clone A and Clone D to determine the preferential survival of one clone.